1. Field of the Invention
The invention relates to inhibitors for the formation of tumor necrosis factor, processes for the preparation thereof by macrophages or mononuclear phagocytes which have been stimulated by lipopolysaccharides, and the use thereof for the treatment and prophylaxis of diseases caused by tumor necrosis factor.
Inflammatory reactions primarily come about by over-expression of immunological mechanisms which are originally present to protect the host organism. It has become clear in recent years that proteins which are formed by the host may in isolated form cause symptoms of disease by bringing about the release of terminal mediators of inflammation. This class of hormone-like proteins is embraced by the term cytokines (Gupta, Scand J Rheumatol Suppl. , (1988) 76, 189). It is now regarded as certain that cytokines are of fundamental importance for the development of inflammatory processes.
2. Description of the Related Art
Among the cytokines, tumor necrosis factor (TNF) has achieved particular importance for the development of acute inflammatory processes because this substance, which is essentially formed by macrophages, is able to induce in mammals a state of shock as is characteristic of bacteremias and sepsis (Tracey et al. Science, 234, (1986), 470). It has furthermore been found that a monoclonal antibody against TNF suppresses lethality in monkeys during bacterial sepsis (Tracey et al., Nature, 330, (1987), 662). It is evident from these findings that TNF is, on the one hand, a sufficient and, on the other hand, an essential factor for the development of many characteristics of endotoxic shock.
The evident linkage between endogenous TNF formation and the development of acute and chronic inflammatory syndromes has led to many attempts to block the endogenous formation of TNF by pharmacological inhibitors. Mention may be made here by way of example of the treatment with steroids, xanthine derivatives and lipoxygenase inhibitors (Zabel et al., Lancet, 23, (1989), 1474). It has also emerged that the cytokine IL 4 is an inhibitor of TNF formation (Essner et al., J. Immunol. 142, (1989), 3857).
The object of the invention was to find new physiological inhibitors with which the endogenous formation of TNF can be inhibited.